Folate (folic acid or vitamin B9) is essential for the biosynthesis of nucleotide bases and for many other methylation reactions. Folic acid is required in increased amounts by rapidly dividing cells, such as cancer cells. Folate receptors can mediate unidirectional transportation of folates into cells. Among the four isoforms of folate receptors identified (α, β, γ, and δ), α and β isoforms of folate receptor are glycosylphosphatidylinositol (GPI)-anchored proteins with two N-glycosylation sites, and both have high affinity (KD of approximately 1 nM) for folate. Elnakat et al., Adv Drug Deliv Rev 2004, 56:1067-1084.
Folate receptor alpha (also referred to as FRα, FR-alpha, FRA, FOLR-1 or FOLR1) is expressed in a variety of epithelial tissues, including those of the choroid plexus, lung, thyroid, kidney, uterus, breast, fallopian tube, epididymis, and salivary glands. Weitman, S D et al. Cancer Res 52: 3396-3401 (1992); Weitman S D et al, Cancer Res 52: 6708-6711.
Gastric or stomach cancer is a cancer that forms in tissues lining the stomach. According to the National Cancer Institute, an estimated 21,320 new cases (more than 13,000 men and 8,000 women) of stomach cancer will be diagnosed in the United States in 2012. Most diagnosed individuals will be over 70 years old. In addition, an estimated 10,540 deaths from stomach cancer will occur in the United States in 2012.
According to the World Health Organization, about 988,000 new cases of stomach cancer were estimated to have occurred in 2008, making it the fourth most common malignancy in the world. More than 70% of cases (713,000 cases) occurred in developing countries (467,000 in men, 246,000 in women). Incidence rates for stomach cancer were highest in Eastern Asia (China, Japan and Korea). Stomach cancer was the second leading cause of cancer death in both sexes worldwide (about 736,000 deaths). The highest mortality rates are estimated in Eastern Asia (28.1 per 100,000 in men, 13.0 per 100,000 in women).
Early detection and treatment of gastric cancer improves survival rates and quality of life. To improve the likelihood of early detection and treatment, a pressing need exists for non-invasive methods for diagnosing gastric cancer, for determining the level of risk of developing gastric cancer, for predicting the progression of gastric cancer, and for treating gastric cancer. The present invention satisfies these needs for folate receptor-alpha-expressing gastric cancer.